Agenus Inc. · NASDAQ:AGEN
Agenus — Investor Day (May 2015)
93 slides from Agenus's investor day presentation, May 14, 2015
Slide 1: Agenus R&D Day May 14th 2015
Agenus R&D Day May 14th 2015 Driving the immune a system to fight cancer and infectious disease
Slide 2: Note Regarding Forward-Looking Statements
Note Regarding Forward-Looking Statements This presentation contains forward-looking statements. These forward-looking statements are subject to risks and uncertainties, including the factors described under the Risk Factors section of our Quarterly Report on form 10-Q filed with the Securities and
Slide 3: Introduction
Introduction Garo Armen, PhD Immuno-Oncology Overview Bob Stein, MD, PhD Tumor Recognition John Castle, PhD Glioblastoma (GBM) Orin Bloch, MD—NW U Agenus / 4-Antibody Robert Burns, PhD Monoclonal Antibodies Marc van Dijk, PhD Checkpoint Modulators (CPMs) Nicholas Wilson, PhD Combination Immunotherap
Slide 4: Three Synergistic Immune-Modulating Platform
Three Synergistic Immune-Modulating Platform Poised to Create Best-in-Class Immunotherapies + Ph 2 in ndGBM + Ph 2 w HerpV Heat Shock Protein-Based Vaccines QS-21 Checkpoint Stimulon® Modulators + Ph 3 Malaria Adjuvant (CPMs) + Ph 3 Shingles
Slide 5: Merck/Agenus CPM Collaboration: Focus on Oncology
Merck/Agenus CPM Collaboration: Focus on Oncology Established April 2014 Uses Agenus’ monoclonal antibody platform Two undisclosed targets Financial considerations Merck pays all R&D costs Up to $100 MM milestones per successful compound Mid-single digit royalties
Slide 6: Incyte/Agenus Immuno-Oncology Collaboration
Incyte/Agenus Immuno-Oncology Collaboration Established February 2015 Initial focus on 4 CPM targets: – GITR and OX40 agonists – TIM-3 and LAG-3 antagonists Financial considerations $60M upfront (with equity investment) Up to $350M in milestones for lead programs Royalty bearing products (TIM-3, LAG
Slide 7: Agenus Pipeline
Agenus Pipeline Partnered Not Partnered
Slide 8: QS-21 Stimulon Saponin Adjuvant
QS-21 Stimulon® Saponin Adjuvant Generates strong antibody and cell-mediated immune responses Safe & well tolerated in >50,000 people
Slide 9: Robust Phase Results with Shingles Vaccine
Robust Phase 3 Results with Shingles Vaccine GSK Merck Efficacy: 97% 50-70% out of 3 people will get shingles in their lifetime Target population: 370M
Slide 10: R&D Day
R&D Day Introduction Garo Armen, PhD Immuno-Oncology Overview Bob Stein, MD, PhD Tumor Recognition John Castle, PhD Glioblastoma (GBM) Orin Bloch, MD—NW U Agenus / 4-Antibody Robert Burns, PhD Monoclonal Antibodies Marc van Dijk, PhD Checkpoint Modulators (CPMs) Nicholas Wilson, PhD Combination Immu
Slide 11: The Immune System… defends from enemies from without
The Immune System… defends from enemies from without
Slide 12: The Immune System… defends from enemies from without & within
The Immune System… defends from enemies from without & within
Slide 13: Immunological Surveillance
Immunological Surveillance Macfarland Burnet (1957): “It is by no means inconceivable that small accumulations of tumour cells may develop and because of their possession of new antigenic potentialities provide an effective immunological reaction with regression of this tumor and no clinical hint of
Slide 14: Accumulated Mutations Drive Cancers
Accumulated Mutations Drive Cancers Various carcinogens (sun, smoke, gamma Approximately 1% rays, etc.) of mutations produce stochastic produce mutant mutations proteins (<0.03% of genome) A handful hit growth- A fraction of these related genes, driving produce potential T-cell malignancy neo-epitop
Slide 15: Cancer- In Limbo between Self & Non-Self
Cancer- In Limbo between Self & Non-Self Mutational Heterogeneity in Cancer Taking off brakes may be enough May need agonists, Unclear how widely vaccines, adjuvants, etc. Immuno-Rx will work Lawrence MS et al. Nature 2013; 499: 214-18 100 mutations per Mbase = 0.01% of genome
Slide 16: Heat-Shock-Protein (HSP)-based Vaccines: Pre-Clinical Overview
Agenus R&D Day Heat-Shock-Protein (HSP)-based Vaccines A strategy for Tumor-Specific Immuno-education Pre-Clinical Overview
Slide 17: The Immune System Can Defeat Cancer
The Immune System Can Defeat Cancer The Observations that led to Agenus TUMOR A TUMOR A or B CELLS INJECTED CELLS INJECTED Tumor mass is resected from mouse Mouse cured of tumor A immune to tumor A Naïve mouse Mouse forms Mouse Cured tumor mass Of Tumor A Mouse cured of Requires immune system tumor
Slide 18: Immunity is Individually Tumor Specific
Immunity is Individually Tumor Specific different methylcolanthrene-induced murine fibrosarcomas Tumors Used to Immunize A BB C C D D E E FF G H H I I J A A + — — — — - e ng B B—+ — — — — l e C C — + — — — - al Ch D D ——+ — — —to E E — — + — — -Used F F — ——+ — — G rs G — — — + — o H m H — — ——+ — u
Slide 19: Heat Shock Protein Fractions Confer Immunity
Heat Shock Protein Fractions Confer Immunity hsp70 hsp90 hsp110 gp96 grp170 CRT Tumor cell Proteins liberated Proteins tested in Heat Shock Proteins (HSP) from tumor cell tumor rejection assays elicit anti-cancer immunity Tumor Rx Rx Challenge Tumor DAY 0 7 14 size MONITOR TUMOR GROWTH Days post tum
Slide 20: Heat Shock Proteins (HSPs)
Heat Shock Proteins (HSPs) Quality Control for the Intracellular Proteome Cellular Peptides Chaperoning by HSPs Mutated / Normal Abundant class of intracellular proteins Constantly sample intracellular proteome Sense and manage misfolded proteins Natural role in immune recognition of damaged cells,
Slide 21: Prophage Mechanism of Action
Prophage Mechanism of Action Cell D8+ T Cell IL-12 NK Cell TNF? MCP-1 IL-1? MIP-1á GM-CSF RANTES NO Modified from
Slide 22: Heat-Shock-Protein (HSP)-based Vaccines: Clinical Overview
Heat-Shock-Protein (HSP)-based Vaccines Personalized Immuno-education Clinical Overview Agenus R&D Day
Slide 23: Prophage confers tumor-specific immunity
Prophage confers tumor-specific immunity Tumor Heat Shock Protein bound tumor antigens Prophage Intradermal injection
Slide 24: Prophage: Sporadic Efficacy in Previous Studies
Prophage: Sporadic Efficacy in Previous Studies Patient remains disease-free at 10+ years Before 16 Months 32 Months Prophage Post-Treatment Post-Treatment Belli F et al., J Clin Oncol 2002;20:4169-4180
Slide 25: Prophage Clinical Summary
Prophage Clinical Summary Autologous Cancer Vaccine Practical logistics Cost-effective manufacture Pharmaceutically tractable Well-tolerated Promising efficacy signal in newly diagnosed GBM Phase 3 ready program with near-term registration opportunity Potential synergy with CPMs
Slide 26: R&D Day
R&D Day Introduction Garo Armen, PhD Immuno-Oncology Overview Bob Stein, MD, PhD Tumor Recognition John Castle, PhD Glioblastoma (GBM) Orin Bloch, MD—NW U Agenus / 4-Antibody Robert Burns, PhD Monoclonal Antibodies Marc van Dijk, PhD Checkpoint Modulators (CPMs) Nicholas Wilson, PhD Combination Immu
Slide 27: Immunological Recognition and Rejection of Tumors
Agenus R&D Day Immunological Recognition and Rejection of Tumors The genetic basis of patient-specific immunity
Slide 28: Next-Generation Sequencing (NGS)
Next-Generation Sequencing (NGS) Tumor DNA sequence data
Slide 29: Next-Generation Sequencing (NGS)
Next-Generation Sequencing (NGS) Tumor DNA sequence data Terabytes of data
Slide 30: Next-Generation Sequencing (NGS)
Next-Generation Sequencing (NGS) Tumor DNA sequence data Terabytes of data EFKHIKAFDRTFANNPGPMVVFATPGM Protein-changing EFKHIKAFDRTFADNPGPMVVFATPGM mutations
Slide 31: Genome Sequencing Costs Have Plummeted!
Genome Sequencing Costs Have Plummeted! The first human genome cost $3 billion and took 10 years. A genome can now be sequenced in one week for $3 thousand
Slide 32: We Can Now Determine Tumor Genomes
We Can Now Determine Tumor Genomes Reoccurring tumor mutation Genes Patient tumors Each dot is a tumor mutation Patient-specific tumor mutations PJ Stephens et al. Nature, 1-5 (2012)
Slide 33: Tumors Typically Have Protein-changing Mutations
Tumors Typically Have 10 To 500 Protein-changing Mutations a m a e o m l l b a l l c o e m r n c o e a i h i o l c s c s p l l y o k r u og e r n c a o e c a a l i e c m r m l l a c o m o d i i rn n a r a a o p r a a h r l e t a t c s l d h e u d g n t e l s e a a n c r d q m i tc ac ap e e m a e a
Slide 34: Tumor Mutations
Tumor Mutations Tumors typically have between 10 and 500 protein mutations Over 98% mutations are unique to the specific tumor DNA Tumor cells mutations
Slide 35: Tumor Mutations
Tumor Mutations Tumors typically have between 10 and 500 protein mutations Over 98% mutations are unique to the specific tumor Identify immunogenic mutations DNA Tumor cells mutations
Slide 36: How Can The Immune System “See” Mutations?
How Can The Immune System “See” Mutations? Many challenges to become an effective neo-antigen DNA mutation in protein Transcribed to RNA Translated to protein Processed by proteasomes Transported to the ER Loaded onto MHCs (must fit) Transported to the cell surface Stay on patient’s MHCs Be sufficie
Slide 37: Cells Displaying Neo-antigens Recognized as Non-self by CD8+ T Cells Can Be Destroyed
Cells Displaying Neo-antigens Recognized as Non-self by CD8+ T Cells Can Be Destroyed
Slide 38: Immunogenic Mutations in Patients
Immunogenic Mutations in Patients GBM patient 020-002 GBM patient 020-006 HLA types HLA types HLA-A*02:01 HLA-A*29:02 HLA-B*35:03 HLA-B*44:03 HLA-C*16:01 HLA-A*01:01 HLA-A*68:01 HLA-B*37:01 HLA-B*51:01 HLA-C*06:02 HLA-C*15:02 Mutations 101 protein mutations 50 expressed 23 HLA presented (immunogenic
Slide 39: Tumors With Many Immunogenic Mutations Respond to Inhibitory CPMs
Tumors With Many Immunogenic Mutations Respond to Inhibitory CPMs Like anti-PD-1 and anti-CTLA-4 Predict response to CTLA4 & PD1 therapies Identify immunogenic mutations DNA Tumor cells mutations
Slide 40: Tumors With Many Immunogenic Mutations Respond to Inhibitory CPMs
Tumors With Many Immunogenic Mutations Respond to Inhibitory CPMs Like anti-PD-1 and anti-CTLA-4 Predict response to CTLA4 & PD1 therapies Identify immunogenic mutations DNA Tumor cells mutations
Slide 41: Mutant Protein Vaccination For Patients With Fewer Immunogenic Mutations
Mutant Protein Vaccination For Patients With Fewer Immunogenic Mutations Predict response Use mutant to CTLA4 & PD1 proteins for therapies vaccination Identify immunogenic muteins DNA Tumor cells mutations
Slide 42: Mutant Peptide Vaccination
Mutant Peptide Vaccination Melanoma 563 expressed 50 of 50 B16F10 cells missense confirmed mutations Exploiting the Mutanome for Tumor Vaccination Castle et al., 2013
Slide 43: Mutant Peptide Vaccination
Mutant Peptide Vaccination Melanoma 563 expressed 50 of 50 Immunize with B16F10 cells missense confirmed mutation peptide mutations Exploiting the Mutanome for Tumor Vaccination Castle et al., 2013
Slide 44: Mutant Peptide Vaccination
Mutant Peptide Vaccination ELISPOT Wild type & mutated 16 of 50 mutations immunogenic Melanoma 563 expressed 50 of 50 Immunize with B16F10 cells missense confirmed mutation peptide mutations Exploiting the Mutanome for Tumor Vaccination Castle et al., 2013
Slide 45: Mutant Peptide Vaccination
Mutant Peptide Vaccination ELISPOT Wild type & mutated 16 of 50 mutations immunogenic Melanoma 563 expressed 50 of 50 Immunize with B16F10 cells missense confirmed mutation peptide mutations Tumor challenge 40% mice survive Exploiting the Mutanome for Tumor Vaccination Castle et al., 2013
Slide 46: Humans and Tumors Are Unique
Humans and Tumors Are Unique The immune system recognizes mutated proteins Tumors harbor a unique set of mutations Mutated proteins are recognized by HSPs Prophage vaccines target tumor- and patient-specific mutations
Slide 47: HSP-based Vaccines Target Multiple Mutations
HSP-based Vaccines Target Multiple Mutations And Function As Personalized, Patient-specific Immunotherapies Prophage Patient individualized tumor vaccine Purify heat-shock proteins (HSPs) complexed with muteins
Slide 48: Benefits
Benefits Prophage inherently captures the individuality of tumors and patients By understanding the process, we: Identify patients who will respond to our therapies Enable immuno-monitoring of patients in our clinical trials Can synthesize fully recombinant individualized vaccines Identify immunogen
Slide 49: R&D Day
R&D Day Introduction Garo Armen, PhD Immuno-Oncology Overview Bob Stein, MD, PhD Tumor Recognition John Castle, PhD Glioblastoma (GBM) Orin Bloch, MD—NW U Agenus / 4-Antibody Robert Burns, PhD Monoclonal Antibodies Marc van Dijk, PhD Checkpoint Modulators (CPMs) Nicholas Wilson, PhD Combination Immu
Slide 50: R&D Day
R&D Day Introduction Garo Armen, PhD Immuno-Oncology Overview Bob Stein, MD, PhD Tumor Recognition John Castle, PhD Glioblastoma (GBM) Orin Bloch, MD—NW U Agenus / 4-Antibody Robert Burns, PhD Monoclonal Antibodies Marc van Dijk, PhD Checkpoint Modulators (CPMs) Nicholas Wilson, PhD Combination Immu
Slide 51: Agenus Integrated Antibody Discovery
Agenus Integrated Antibody Discovery Dedicated to Making Best in Class Antibody Drugs Target Retrocyte Display™ Yeast Display (SECANT®) Phage Display Fully human repertoire Display of full length IgG through ScFv or Fab format binding displayed on mouse pre-B cells biotin attachment Massive diversit
Slide 52: Key Components – Retrocyte Display
Key Components – Retrocyte Display™ Retroviral transduction of human heavy and light chain antibody genes huIgG VH á â Ig ——Ig -Ig Igá â Mouse pre-B cells huIgG Multi- Top Leads VL Natural folding, parameter pairing, and Fully human high screening anchoring diversity stable methods antibody librarie
Slide 53: Key Components – SECANT Yeast Display
Key Components – SECANT® Yeast Display Biotinylated antibody is secreted and captured by the avidin on the surface of the same cell Biotin Ligase
Slide 54: Key Components – SECANT Yeast Display
Key Components – SECANT® Yeast Display A library of yeast cells displaying captured antibodies is exposed to fluorescently labeled target antigen. Yeast cells displaying an antibody recognizing the target are isolated by FACS Multiple parameter FACS selection
Slide 55: Key Components – SECANT Yeast Display
Key Components – SECANT® Yeast Display After selection by FACS the isolated yeast cell will continue to grow, causing avidin to progressively disappear and antibody to be released into the medium Biotin Ligase
Slide 56: Key Components – Phage Display
Key Components – Phage Display Phage Display Highlights Use of VH and VL gene repertoires in well-established • Workhorse technology phage-display screening cycle • Very large libraries to provide maximum diversity Flexible selection conditions (pH, temperature) Primary utility generation of hit pan
Slide 57: Key Components – Bi-specific Format
Key Components – Bi-specific Format Mix & screen technology, product-ready format Single-point mutant, homodimeric formats expressed and mixed under permissive conditions allows recombination into bi-specific formats with high efficiency Application combinations are key in immuno-oncology Generates
Slide 58: Modular Platform Components Interchangeable and Complementary
Modular Platform Components Interchangeable and Complementary Key Antibody Discovery Deployable Agenus Platform Objective Process Steps Components Lead Retrocyte SECANT® Speed & Phage Display Generation Display™ Yeast Display Diversity Retrocyte Efficacy, Lead Fc Engineering Differentiation Display™
Slide 59: Agenus Integrated Discovery Platform
Agenus Integrated Discovery Platform Retrocyte Display™ Yeast Display (SECANT®) Phage Display Fully human repertoire Display of full length IgG through ScFv or Fab format displayed on mouse pre-B cells biotin attachment Massive diversity >1010 Antibody library 5x109 Antibody library Differentiated s
Slide 60: R&D Day
R&D Day Introduction Garo Armen, PhD Immuno-Oncology Overview Bob Stein, MD, PhD Tumor Recognition John Castle, PhD Glioblastoma (GBM) Orin Bloch, MD—NW U Agenus / 4-Antibody Robert Burns, PhD Monoclonal Antibodies Marc van Dijk, PhD Checkpoint Modulators (CPMs) Nicholas Wilson, PhD Combination Immu
Slide 61: Targets Across the Spectrum of Tumor Immunity
Targets Across the Spectrum of Tumor Immunity Equipped to treat a range of human cancers Modified Chen et al., 2013 *Anti-OX40 *Anti-GITR *Anti-TIM-3 *Anti-LAG-3 Novel Platforms Vaccine Platforms Anti-PD1 Anti-CTLA-4 Partnered with INCY: GITR, OX40 agonist antibodies and TIM3, LAG3 antagonist antibo
Slide 62: Antibody Discovery at Agenus
Antibody Discovery at Agenus Antibody Discovery Platforms Key Filters: Examples: Target Binding Recombinant proteins, cell lines (over-expressing, endogenous) Species cross-reactivity Human/NHP/rodent Many Hits Target selectivity Related family members (100s+) CDR diversity from panning Sequencing (
Slide 63: Antibodies Are Naturally Bifunctional
Antibodies Are Naturally Bifunctional Variable region defines interaction with target antigen IgG Fc region dictates half-life, antibody dependent cellular cytotoxicity (ADCC), CDC, phagocytosis (ADCP)… Activating Inhibitory Activating Modified: Pietersz et al., Nature Review Drug Discovery 2012
Slide 64: Two Functionally Distinct Classes Of Fc Receptors
Two Functionally Distinct Classes Of Fc? Receptors: Activating And Inhibitory Example: Rituxan Clynes et al., Nat Med 2000 Nimmerjahn and Ravetch Nat. Rev. Imm. 2008
Slide 65: Inhibitory FcγRIIB Mediates Receptor Forward Signaling
Inhibitory Fc?RIIB Mediates Receptor Forward Signaling By Anti-TNFR Antibodies Cross-linking (Forward signaling) E.g: Anti-CD40/DR5 Wilson NS et al., Cancer Cell, 2011 Li et al., Science 2011 White et al., JI 2011 Nimmerjahn and Ravetch Nat. Rev. Imm. 2008
Slide 66: Canonical View of GITR Forward Signaling in T Cells
Canonical View of GITR Forward Signaling in T Cells Naïve GITR -L T cell GITR expression upregulated Initial 24-72 hrs priming Activated mature DC No GITR stimulus GITR Secondary engagement expansion Effector phase Reduced T cell Enhanced effector T cell expansion/survival expansion/survival Decreas
Slide 67: Model for GITR Agonist Immunotherapy of Cancer
Model for GITR Agonist Immunotherapy of Cancer Cohen & Schaer et al. PloS ONE 2010 May 3;5(5) Schaer et al. Cancer Immunology Research 2013 Nov 5 Schaer, Murphy & Wolchok Current Opinion in Immunology 2012, 24:217–224
Slide 68: Fc Receptors Contribute To The Activity Of Antibodies
Fc? Receptors Contribute To The Activity Of Antibodies Targeting Immune Regulatory Molecules TNFRs ? Modified: Mellman et al., Nature 2011 Modified: Pietersz et al., Nature Review Drug Discov 2012 Partnered with INCY: GITR, OX40 agonist antibodies and TIM3, LAG3 antagonist antibodies
Slide 69: Preclinical: Anti-OX40 and Anti-GITR Require Intact FcγR Interactions
Preclinical: Anti-OX40 (OX86) and Anti-GITR (DTA-1) Require Intact Fc?R Interactions to Exert Anti-Tumor Activity In Vivo Colon26 model Control DTA-1 mIgG2a DTA-1 (N297A) 700 700 700 600 600 600 ) (mm 500 500 500 Anti-GITR 400 400 400 Volume 300 300 300 200 200 200 100 100 100 0 0 0 0 3 6 9 12151821
Slide 70: Old Paradigm: Activating FcγRs Enhance Cytotoxic Antibodies
Old Paradigm: Activating Fc?Rs Enhance Cytotoxic Antibodies, Inhibitory Fc?RIIB Facilitates Antibody-Mediated Forward Signaling Anti-CD20 Anti-CD40 Anti-EGFR Anti-DR4 Anti-Her2 Anti-DR5 Anti-FGFR3 Anti-CD27 Anti-CD19 Anti-CD30 Other… Anti-CD95 Modified from: Nimmerjahn F and Ravetch, J Cancer Immuno
Slide 71: Activating FcγRs Are Required for Anti-tumor Activity of GITR and OX40 Antibodies
Activating Fc?Rs Are Required for Anti-tumor Activity of Agonist GITR and OX40 Antibodies Anti-GITR Anti-OX40 Bulliard et al., JEM 2013 Colon26 tumor model Bulliard et al., ICB 2014 Control Wild type 100% CR
Slide 72: GITR and OX40 Are Expressed By Multiple Immune Cell Subsets
GITR and OX40 Are Expressed By Multiple Immune Cell Subsets Within The Tumor Microenvironment Croft et al., Ann. Rev. of Immunol. 2010 Restifo et al., Cancer Res 2012 Cell type GITR OX40 B cells ++ +/- Naive CD4 T cells +—Naive CD8 T cells +—Regulatory T cells ++++ +++ Activated CD4 T cells +++ ++ A
Slide 73: Intra-Tumoral Regulatory T Cells Express High Levels of GITR and OX40
Intra-Tumoral Regulatory T Cells Express High Levels of GITR and OX40. Antibody Treatment Leads to Depletion Bulliard et al., JEM 2013 Colon26 model Bulliard et al., ICB 2014 GITR expression OX40 expression Tregs Tregs
Slide 74: Preclinical: Selective Intratumoral Treg Depletion is Rapid
Preclinical: Selective Intratumoral Treg Depletion is Rapid, and Requires Fc?R Co-engagement Colon26 model Kinetics of Tregs depletion (within the tumor) 7.0 Control CD4+ 6.0 DTA-1 mIgG2a Tumor 5.0 DTA-1 N297A FoxP3+ cells 4.0 T of 3.0 node 2.0 28-fold Lymph Density 1.0 0.0 0 1 2 3 4 5 6 Days post-t
Slide 75: Translation to Human Tumors
Translation to Human Tumors: Intratumoral Regulatory T Cells Overexpress OX40 Mouse Healthy Donor Tumor Colon tumor model (CT26) PBMCs TILs Tconv Treg Tconv Treg A D B E C F Bulliard Y et al., JEM 2013 Waight et al., Agenus unpublished data
Slide 76: Antibody Co-Engagement of FcγRs Depletes Intra-Tumoral Tregs
Antibody Co-Engagement of Fc?Rs Depletes Intra-Tumoral Regulatory T Cells (Examples: GITR & OX40) GITR & OX40 agonist antibodies deplete intratumoral Tregs Smyth M. et al., ICB 2014 Bulliard Y. et al., ICB 2014 Bulliard Y. et al., JEM 2013 Simpson et al., JEM 2013 Shelby et al., Can. Immunol. Res. 2
Slide 77: Targets Across the Spectrum of Tumor Immunity
Targets Across the Spectrum of Tumor Immunity Equipped to treat a range of human cancers Modified Chen et al., 2013 *Anti-OX40 *Anti-GITR *Anti-TIM-3 *Anti-LAG-3 Novel Platforms Vaccine Platforms Anti-PD1 Anti-CTLA-4 Partnered with INCY: GITR, OX40 agonist antibodies and TIM3, LAG3 antagonist antibo
Slide 78: Clinical Candidate: Anti-GITR Agonist Antibody (Planned IND 2015)
Clinical Candidate: Anti-GITR Agonist Antibody (Planned IND 2015) Goal: Differentiated mechanism of action for best-in-class potential Example: Enhanced poly-functional T cell response by GITR agonism Donor ID#XXXX Isotype CD4+ 3% 3% 0% 1% T cells 12% 2% 10% 11% 3% 3% CD8+ T cells ã IFN 12% 5% Refer
Slide 79: Clinical Candidate: Anti-OX40 Agonist Antibody (Planned IND 2016)
Clinical Candidate: Anti-OX40 Agonist Antibody (Planned IND 2016) Goal: Differentiated mechanism of action for best-in-class potential Example: Anti-OX40 antibody-mediated T cell modulation n 8 i o nduct 6 I e i n 4 k o Cyt 2 ld o 0 F y e12 s d p b b u o t y A A n i b o f f e t s e e g n I A a R R o
Slide 80: Generating High-quality Antibodies is a Great Start
Generating High-quality Antibodies is a Great Start Understanding the Target Biology is also Critical (e.g., TIM-3) Complex biology Preclinical data ? Days post tumor implantation Sakuishi K et al. JEM 2010 The complexity is both a challenge and an opportunity!
Slide 81: Checkpoints – The Beginning of Understanding
Checkpoints – The Beginning of Understanding B7-1/CD80 4-1BB/CD137 TIM3 2B4/CD244/SLAMF4 B7-2/CD86 4-1BB Ligand GAL-9 BLAME/SLAMF8 B7-H1/PD-L1 CD27 CD2 CD2 B7-H2/B7RP1/ICOS-L CD27 Ligand/CD70 CD7 CD2F-10/SLAMF9 B7-H3 CD30 CD53 CD48/SLAMF2 B7-H4 CD30 Ligand CD82/Kai-1 CD58/LFA-3 B7-H5/VISTA CD40 CD90
Slide 82: R&D Day
R&D Day Introduction Garo Armen, PhD Immuno-Oncology Overview Bob Stein, MD, PhD Tumor Recognition John Castle, PhD Glioblastoma (GBM) Orin Bloch, MD—NW U Agenus / 4-Antibody Robert Burns, PhD Monoclonal Antibodies Marc van Dijk, PhD Checkpoint Modulators (CPMs) Nicholas Wilson, PhD Combination Immu
Slide 83: CPM Combinations
CPM Combinations agenus
Slide 84: Combination Therapies Likely Key to Success
Combination Therapies Likely Key to Success With CTLA-4 and PD-1 antagonists, different patients respond differently – Differences in responses to each CPM or combo – Differences in time course of response – Reflects mutational burden, in part Studies with proxy TAAs such as NY-ESO-1 demonstrate het
Slide 85: Cancer- In Limbo between Self & Non-Self
Cancer- In Limbo between Self & Non-Self Mutational Heterogeneity in Cancer Taking off brakes may be enough May need agonists, Unclear how widely vaccines, adjuvants, etc. Immuno-Rx will work Lawrence MS et al. Nature 2013; 499: 214-18 100 mutations per Mbase = 0.01% of genome
Slide 86: Checkpoints and Vaccines Synergize
Checkpoints and Vaccines Synergize OX40 agonist and vaccine in mice Vaccine + CTLA-4 inhibitor (ipilimumab) better than either alone in prostate cancer Jensen et al., 2010 Semin Oncol. 37(5):524-32. Ipi monotherapy failed in Ph 3 (no stat. sign. vs. placebo) Importantly: 20% of patients alive at 80
Slide 87: HSPPC-96 + Anti-CTLA-4 Ab in Mouse SM1 Therapy
HSPPC-96 + Anti-CTLA-4 Ab in Mouse SM1 Therapy Set-up gp96 gp96 gp96 gp96 gp96 gp96 Day 0 3 4 6 7 9 10 12 15 18 Monitor tumor growth SM1 Tumor Ab Ab Ab Challenge (ID) Results SM1 (breast cancer) Buffer Antibody gp96 Antibody + gp96 (mm) 25 25 0/7 (0%) 1/7 (14%) 1/6 (17%) 6/7 (86%) 20 20 15 15 diamet
Slide 88: Realizing New Optimized Combination Strategies
Realizing New Optimized Combination Strategies An armamentarium to tackle a range of human malignancies Example: PD-1 and CTLA-4 combination Agenus’ diverse I-O portfolio Partnered with INCY: GITR, OX40 agonist antibodies and TIM3, LAG3 antagonist antibodies Postow M et al., NEJM 2015 SMIs
Slide 89: Translational Medicine in Immuno-Oncology
Translational Medicine in Immuno-Oncology What is the initial pathobiology? Has the patient seen the tumor as non-self? What immuno-suppressive mechanisms are blunting recognition of tumor? What checkpoint processes will block tumor killing? Those already in place and those induced by therapy What c
Slide 90: R&D Day
R&D Day Introduction Garo Armen, PhD Immuno-Oncology Overview Bob Stein, MD, PhD Tumor Recognition John Castle, PhD Glioblastoma (GBM) Orin Bloch, MD—NW U Agenus / 4-Antibody Robert Burns, PhD Monoclonal Antibodies Marc van Dijk, PhD Checkpoint Modulators (CPMs) Nicholas Wilson, PhD Combination Immu
Slide 91: R&D Day
R&D Day Introduction Garo Armen, PhD Immuno-Oncology Overview Bob Stein, MD, PhD Tumor Recognition John Castle, PhD Glioblastoma (GBM) Orin Bloch, MD—NW U Agenus / 4-Antibody Robert Burns, PhD Monoclonal Antibodies Marc van Dijk, PhD Checkpoint Modulators (CPMs) Nicholas Wilson, PhD Combination Immu
Slide 92: Three Synergistic Immune-Modulating Platform
Three Synergistic Immune-Modulating Platform Poised to Create Best-in-Class Immunotherapies + Ph 2 in ndGBM + Ph 2 w HerpV Heat Shock Protein-Based Vaccines QS-21 Checkpoint Stimulon® Modulators + Ph 3 Malaria Adjuvant (CPMs) + Ph 3 Shingles
Slide 93: Agenus R&D Analysts Day
Agenus R&D Analysts Day May 14th. 2015 Driving the immune a system to fight cancer and infectious disease