Agenus Inc. · NASDAQ:AGEN
Agenus — Investor Day (November 2015)
114 slides from Agenus's investor day presentation, Nov 19, 2015
Slide 1: Agenus R&D Day
Agenus R&D Day November 19, 2015 New York, NY Exhibit 99.1
Slide 2: Forward-Looking Statements
Forward-Looking Statements This presentation contains forward-looking statements, including statements regarding the Company’s pending acquisition of XOMA Corporation’s antibody pilot plant manufacturing facility and capabilities. These forward-looking statements are subject to risks and uncertainti
Slide 3: Agenda
Agenda Agenus R&D Day | Nov 19, 2015 Registration Agenus Strategy – Armen R&D Overview – Stein Immunomodulatory antibodies at Agenus – Wilson Next generation mAb discovery incorporating structure-based design – van Dijk, Underwood, Duncan Next Steps with Prophage™ in ndGBM – Goldberg AutoSynVax™: Ne
Slide 4: Agenus Strategy
Agenus Strategy Garo Armen, PhD Chairman and CEO
Slide 5: Garo H. Armen, PhD
Garo H. Armen, PhD Dr. Garo H. Armen serves as Chairman and Chief Executive Officer of Agenus Inc., which he co-founded in 1994. From mid-2002 through 2004, Garo, in addition to his responsibilities at Agenus, served as Chairman of the Board of Directors for the biopharmaceutical company Elan Corpor
Slide 6: The Beginning of Agenus
The Beginning of eenus
Slide 7: Agenus: months of progress
Agenus: 6 months of progress May 14th November 19th # of Partnered Programs 4 with Incyte 2 with Merck 7 with Incyte 2 with Merck* Capabilities 2 antibody platforms 4 antibody platforms Cell-line development Antibody manufacturing** Lead Programs Prophage™ 6 CPM programs Prophage™ AutoSynVax™ 15 CPM
Slide 8: Positioned to create value for patients and investors
Positioned to create value for patients and investors Autologous Vaccines Strong Financial Position CPM Assets to Enter Clinic Marquee Partnerships Broad & Integrated Capabilities Next Generation Programs Expanded Pipeline Planning Randomized Prophage™ Trials Core Foundation in Immuno-Oncology Agenu
Slide 9: R&D Overview
ii. R&D Overview Agenus & Immuno-Oncology: Enlisting the Immune System in the Battle against Cancer Robert B. Stein, MD, PhD CSO & Head of R&D
Slide 10: Robert B. Stein, MD, PhD
Robert B. Stein, MD, PhD As Chief Scientific Officer and Head of R&D at Agenus Inc., Dr. Robert Stein is responsible for all aspects of R&D, including the antibody platforms. He joined Agenus in January 2014. Over his 35 years of experience in the biopharmaceutical industry he played a pivotal role
Slide 11: Advanced cancers are becoming vulnerable to immune therapies
Advanced cancers are becoming vulnerable to immune therapies! Agenus R&D Day | Nov 19, 2015 Control Standard or other therapy Checkpoint blockade Combination % Survival Time
Slide 12: Early recognition of role of immune system in cancer control
Early recognition of role of immune system in cancer control… “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 clinica
Slide 13: Mutations drive malignant transformation
Mutations drive malignant transformation – becoming cancerous Mutations Agenus R&D Day | Nov 19, 2015
Slide 14: Small fraction of mutations immunologically detectable
Small fraction of mutations immunologically detectable Various carcinogens (sun, smoke, gamma rays, etc.) produce stochastic mutations (<0.03% of genome) A fraction of these produce potential T-cell neo-epitopes – potential basis for immune rejection (1-20+) A handful hit growth-related genes, drivi
Slide 15: Cancers are much more self than non-self
Lawrence MS et al. Nature 2013; 499: 214-18 Cancers are much more “self” than “non-self” In “highly mutant” tumors, <0.01% of the genome is mutant!! Agenus R&D Day | Nov 19, 2015
Slide 16: Mutations can produce muteins which can be neo-epitopes
Median per tumor DNA Mutations can produce “muteins” which can be neo-epitopes Agenus R&D Day | Nov 19, 2015 John Castle, Agenus unpublished data About 1% of point mutations encode mutant proteins About 5-10% of these are potential T-cell neo-epitopes These neo-epitopes have the potential to trigger
Slide 17: The Problem – metaphorically speaking
The Problem – metaphorically speaking…… - Aleksandr Solzhenitsyn, The Gulag Archipelago 1918-1956 “If only it were all so simple! If only there were evil people somewhere insidiously committing evil deeds, and it were necessary only to separate them from the rest of us and destroy them. But the line
Slide 18: The immune system versus cancer
Normal Transformed The immune system versus cancer Agenus R&D Day | Nov 19, 2015
Slide 19: The immune system versus cancer: immune surveillance
Normal Transformed The immune system versus cancer X Immune Surveillance ELIMINATION by immune system Agenus R&D Day | Nov 19, 2015
Slide 20: The immune system versus cancer: equilibrium
Normal Transformed The immune system versus cancer Select for Immune Resistance X Early Stage EQUILIBRIUM with immune system (dormancy) Immunoediting Agenus R&D Day | Nov 19, 2015
Slide 21: Agenus' HSP-based vaccines can wake the slumbering giant
Agenus’ HSP-based vaccines can “wake the slumbering giant” Agenus R&D Day | Nov 19, 2015 Effectively enhancing immunity against tumor-specific neo-epitopes
Slide 22: The immune system & cancer - survival of the stealthiest
The immune system & cancer - survival of the stealthiest Strong immune selection exerted on cancer cells Cancers which could be recognized as “non-self” eliminated unless they evade immunity Avoid or blunt immune recognition Block destruction by immune mechanisms Advanced cancers have defeated natur
Slide 23: The immune system versus cancer: escape
Normal Transformed X Early Stage Late Stage EQUILIBRIUM with immune system (dormancy) ESCAPE from immune system (progression) The immune system versus cancer Immuno-evasive adaptations Immunoediting Select for Immune Resistance
Slide 24: Immune regulation through checkpoints
Immune response Immune regulation through checkpoints Agenus R&D Day | Nov 19, 2015 T Cells and other Immune cells Inhibitory Receptors Checkpoints involve a range of receptors, usually on T-cells, activated by ligands on APCs or other cell types Checkpoint processes act to tailor immune activity to
Slide 25: Cancers hijack checkpoint processes to evade immunity
Cancers hijack checkpoint processes to evade immunity Agenus R&D Day | Nov 19, 2015 T Cell Tumeh et al. Nature 515, 568–571 (27 November 2014) Inhibited antitumor immunity
Slide 26: Checkpoint modulating antibodies (CPMs) reset the odds
Checkpoint modulating antibodies (CPMs) reset the odds Agenus R&D Day | Nov 19, 2015 Tumeh et al. Nature 515, 568–571 (27 November 2014) Enhanced antitumor immunity
Slide 27: Choosing significant CP & CP-L targets key to I-O success
Choosing significant CP & CP-L targets key to I-O success 7 Disclosed CPM programs 4 partnered with INCY 3 Agenus retained(*) 8 Undisclosed CPM programs 2 partnered with MRK 3 partnered with INCY (**) 3 Agenus retained PD-1 CTLA-4 LAG-3 OX-40 GITR B7-1/CD80SIRPa BAFF/BLySCD200CD48/SLAMF2 B7-2/CD86CD
Slide 28: Combination therapies likely key to success in immuno-oncology
Tumors differ in the nature and extent of non-self epitopes Immune system-tumor interaction varies between patients Immune system-tumor interactions evolve with time Immuno-editing, Checkpoints, other immuno-evasive or immuno-suppressive strategies A complex, redundant network of processes shape imm
Slide 29: Agenus programs broadly address therapeutic opportunities in I-O
Agenus programs broadly address therapeutic opportunities in I-O Modified Chen et al., 2013 Agenus R&D Day | Nov 19, 2015 Vaccines
Slide 30: Optimizing our monoclonal antibody platform
Integrated Fast Flexible Scalable Cost-effective Lead Generation Lead Optimization Drug Profiling IND Enabling Early Development Registrational Development Optimizing our monoclonal antibody (mAb) platform Phage Display GMP Production* Cell Line Dev. Retrocyte Display™ Duobody® HT-CHO Structure-Base
Slide 31: Agenus 2.0 – immuno-therapy re-envisioned
Organization Heat-Shock-Protein-based Cancer Vaccines QS21 Saponin Adjuvant Platform Monoclonal Antibody Platform & Capabilities Checkpoint Modulators Partnerships Pipeline Financials Prospects: best-in-class combination immuno-therapies Agenus 2.0 – immuno-therapy re-envisioned Agenus R&D Day | Nov
Slide 32: Immunomodulatory antibodies at Agenus
iii. Immunomodulatory antibodies at Agenus Nick Wilson, PhD Senior Director, T cell Biology
Slide 33: Nicholas Wilson, PhD
Nicholas Wilson, PhD Since August 2014, Nicholas Wilson has served as Agenus Inc.’s Senior Director, T Cell Biology. With over 10 years of industry-related research experience, Nicholas has led multi-functional teams of research and translational scientists focused on drug discovery and development
Slide 34: Topics in focus
Topics in focus Update on our immuno-modulatory CPM antibody portfolio Combination opportunities with two distinct anti-CTLA-4 antagonist antibodies Next-generation Fc optimized immunomodulatory antibodies with improved function Harnessing our discovery antibody platforms to target pathways involved
Slide 35: Immune & non-immune cells require multiple intervention modes
Immune & non-immune cells require multiple intervention modes Vaccines LMW QS21 Antibodies Rational combinations: Tumor Agenus R&D Day | Nov 19, 2015 Adapted from: Pattabiraman DR et al., 2014
Slide 36: Development candidate selection: finding the needle in the haystack
Development Candidate selection: finding the needle in the haystack Key Filters: Examples: Target binding Recombinant proteins, cell lines (overexpressing, endogenous) Species cross-reactivity Human/NHP/rodent Target selectivity Related family members CDR diversity from panning Sequencing (NGS) Bloc
Slide 37: Checkpoints shape anti-cancer immune responses
Anti-PD1 ** Anti-CTLA-4** Anti-OX40* Anti-GITR* Anti-TIM-3* Anti-LAG-3* Anti-CEACAM1 2 NME 2 NME^ 3 NME* 2 NME *Antibodies partnered with Incyte: GITR, OX40 (agonists) TIM3, LAG3 (antagonists) and three undisclosed targets **Antibodies partnered with Recepta for certain South American territories ^M
Slide 38: Carcinoembryonic Antigen Cell Adhesion Molecule (CEACAM1)
Carcinoembryonic Antigen Cell Adhesion Molecule 1 (CEACAM1) Combines effectively with surrogate antibodies targeting TIM-3 and PD-1 Status: Lead Optimization Exclusively licensed from Diatheva Expressed by activated T cells, NK cells Potent co-inhibitory receptor Overexpressed by tumor cells Expands
Slide 39: Anti-CTLA-4 antagonist antibodies and combination opportunities
Anti-CTLA-4 antagonist antibodies and combination opportunities Functional Properties Promote T cell function to weakly immunogenic tumor antigens Cooperate with other checkpoint modulators, targeted therapies and vaccines Lead candidates with intended Fc g receptor functionality (ADCC or ADCP) Tran
Slide 40: HSP-based vaccines combine with anti-CTLA-4 antagonist antibodies
HSP-based vaccines combine with anti-CTLA-4 antagonist antibodies Murine breast cancer tumor model 87% CR Example: Prophage™ Series Internal data (unpublished) Vaccine Antibody Agenus R&D Day | Nov 19, 2015
Slide 41: Enhanced T cell-dependent vaccine response in primate model
Enhanced T cell-dependent vaccine response in primate model Hepatitis B vaccine + anti-CTLA-4 antibody Candidate A (IgG1) Candidate B (IgG2) Agenus R&D Day | Nov 19, 2015 Internal data (unpublished) Vaccine Antibody Candidate A (N=6) Candidate B (N=6) Candidate and HBsAg vaccination
Slide 42: Basic monoclonal antibody (mAb) scaffold
Basic monoclonal antibody (mAb) scaffold Agenus R&D Day | Nov 19, 2015 Heavy Chain (blue) Light Chain (green) Half-life Effector function (ADCC, ADCP, CDC) etc. Disulfide Bonds Fab (fragment, antigen binding) region Fv (fragment variable) region; Affinity, epitope, pH dependent binding etc. Fc (frag
Slide 43: Anti-CTLA-4 antibodies deplete intra-tumoral regulatory T cells
Anti-CTLA-4 antibodies deplete intra-tumoral regulatory T cells Agenus R&D Day | Nov 19, 2015 NK CELL TREG CTLA-4 Antibody FcRs TREG MACROPHAGE CTLA-4 Antibody FcRs NK cell Regulatory T cell Neutrophil Macrophage TUMOR ADCP ADCC Regulatory T cell depletion Antibody-Dependent Cellular Phagocytosis (A
Slide 44: IgG1 and IgG2 anti-CTLA-4 mAbs engage distinct effector functions
IgG1 and IgG2 anti-CTLA-4 mAbs engage distinct effector functions FcgRIIIA Signaling FcgRIIA Signaling ADCC ADCP Phagosome Cytotoxic granules Antibody FcүRIIIA FcүRIIA Antibody Agenus R&D Day | Nov 19, 2015 Candidate A Candidate B Candidate A (IgG1) Candidate B (IgG2)
Slide 45: Topics in focus
Topics in focus Update on our immuno-modulatory CPM antibody portfolio Combination opportunities with two distinct anti-CTLA-4 antagonist antibodies Next-generation Fc optimized immunomodulatory antibodies with improved function Harnessing our discovery antibody platforms to target pathways involved
Slide 46: Two functionally distinct classes of Fcg receptors
Agenus R&D Day | Nov 19, 2015 CELL ADCC Example: Rituxan NK CELL & MACROPHAGE FcγRI FcγRIIA FcγRIIIA FcγRIIB Adapted from: Clynes et al., Nat. Med. 2000 Adapted from: Nimmerjahn and Ravetch NRI 2008 Two functionally distinct classes of Fcg receptors: activating and inhibitory
Slide 47: Optimizing next-generation monoclonal tumor targeted antibodies
Fab Fv Fc VH VL CH1 CH2 CH3 Affinity, epitope, pH dependent binding etc. Half-life Effector function (ADCC, ADCP, CDC) etc. Rituximab versus Obinutuzumab (IgG1 vs afucosylated IgG1) CLL Goede et al., NEJM 2014 Current industry focus Agenus R&D Day | Nov 19, 2015 Optimizing next-generation monoclonal
Slide 48: Current version versus Fc optimized variants
Current version versus Fc optimized variants Internal data (unpublished) Anti-PD-1 Anti-CTLA-4 Agenus R&D Day | Nov 19, 2015 Next-generation immunomodulatory antibodies through optimization of the IgG framework
Slide 49: Exploring alternate pharmacology of immune checkpoint modulators
Exploring alternate pharmacology of immune checkpoint modulators Agenus R&D Day | Nov 19, 2015 Key Filters: Examples: Target binding Recombinant proteins, cell lines (overexpressing, endogenous) Species cross-reactivity Human/NHP/rodent Target selectivity Related family members CDR diversity from pa
Slide 50: Less Yang, More Yin
Less Yang, More Yin Agenus R&D Day | Nov 19, 2015 Cancer, Infectious disease Inflammation, autoimmunity & transplantation Targeting co-stimulatory pathways CD28 CD80 CD86 CTLA-4 ICOS ICOS-L TCRα TCRβ PMCH OX40 OX40L LFA-3 CD2 LFA-1 ICAM Tuning in the reverse pharmacology of antibodies targeting the
Slide 51: Targeting the pathogenic role of the OX40-OX40 ligand axis
Targeting the pathogenic role of the OX40-OX40 ligand axis Agenus R&D Day | Nov 19, 2015 Role of T cell co-stimulatory pathways in autoimmunity and transplantation Example: OX40L-OX40 Interactions Anti-OX40 antagonist antibody Therapeutic opportunities: Transplant rejection, vasculitis, asthma, rheu
Slide 52: Where to next
Where to next… Identify and validate targets to combine with current portfolio Leverage positive and negative immune regulators to build integrated portfolio Aggressively pursue next-generation and first-in-class opportunities Expert research team and smart risk taking will drive innovation Optimal
Slide 53: Next generation mAb discovery incorporating structure-based design
Next generation mAb discovery incorporating structure-based design Marc van Dijk, PhD CTO, 4-Antibody Dennis Underwood, PhD VP, Molecular and Information Systems Alex Duncan, PhD VP, Preclinical Development
Slide 54: Marc van Dijk, PhD
Marc van Dijk, PhD Agenus R&D Day | Nov 19, 2015 Marc van Dijk is Chief Technology Officer of 4-Antibody, a subsidiary of Agenus Inc., where he developed Retrocyte display™, Agenus’ proprietary antibody discovery platform. Previously, he led the antibody discovery programs in the alliance with the L
Slide 55: Multiple, integrated antibody display and optimization technologies
Multiple, integrated antibody display and optimization technologies Platform Format Key properties Primary use Phage Display ScFv F’Ab Very high diversity Rapid selection Flexible screening conditions (pH, T°) Hit panel generation Epitope scouting Affinity improvement SECANT® Yeast Display Full Leng
Slide 56: Agenus integrated antibody platform: horses for courses
✓ ✓ ✓ ✓ ✓ ✓ Agenus integrated antibody platform: horses for courses Hit Generation Lead Identification Lead Optimization Candidate Verification Pilot Scale Production* Target Validation Retrocyte Display™ (mammalian) 4-AB HT-CHO Internal Soluble mAbs * Subject to closing; expected December 2015 Agen
Slide 57: Multiple platforms enable precise tuning of every desired property
Epitope coverage Binding affinity Throughput Scalability Drug–like properties Biological function Multiple platforms enable precise tuning of every desired property Iontas Phage Display HT-CHO Soluble mAbs SECANT® Yeast Display Agenus R&D Day | Nov 19, 2015 Retrocyte Display™ (mammalian)
Slide 58: SECANT Yeast Display enables target validation and more
SECANT® Yeast Display enables target validation and more Yeast Display (SECANT®) Display of full length IgG through biotin attachment Highlights >109 library diversity Multi-parameter FACS Selection Rapid soluble mAb panel generation Target validation Hit generation/Format engineering Target Validat
Slide 59: Phage Display provides maximal diversity for hit generation
Phage Display provides maximal diversity for hit generation Agenus R&D Day | Nov 19, 2015 Phage Display (Iontas) ScFv or Fab format Highlights Very high diversity (>1010) ScFv or F’ab format Flexible selection conditions (pH, To) Hit panel generation Epitope scouting Affinity improvement j j Target
Slide 60: Retrocyte Display
Retrocyte Display™ Full length, fully human repertoire displayed on mouse pre-B cells 109 Antibody libraries Highlights Natural folding / pairing Rapid chain exchange Multi-parameter FACS Selection Well behaved mAbs CMC optimization Sequence optimization Target Validation Hit Generation Lead Identif
Slide 61: HT-CHO expands lead optimization to Fc selection
HT-CHO expands lead optimization to Fc selection Agenus R&D Day | Nov 19, 2015 HT-CHO Optimized proprietary High-Throughput mAb expression Fc-regions Seeking the optimal MOA >20 different Fc-options Rapid reconfiguration Target Validation Hit Generation Lead Identification Lead Optimization Candidat
Slide 62: NGS and informatics integrate information across platform
NGS and informatics integrate information across platform j Structural biology Lead Identification j Next Generation Sequencing Genomics and bioinfomatics workflow Millions of Ab equences Sample Raw NGS data NGS data process- ing Processed data Data Interpre-tation Interpreted data File size Can be
Slide 63: Integrated platform provides speed, flexibility for antibody discovery
Lead Generation Lead Optimization Drug Profiling IND Enabling Exploratory Development Confirmatory Development Integrated platform provides speed, flexibility for antibody discovery Fab Fv Fc VH VL CH1 CH2 CH3 Phage Display Retrocyte Display™ SECANT® Yeast Display Duobody® HT-CHO Structure-Based Opt
Slide 64: Dennis Underwood, PhD
Dennis Underwood, PhD Dennis Underwood is Agenus Inc.’s Vice President of Molecular and Info Systems. Dennis brings over 30 years of industry experience in Big Pharma, biotech, and entrepreneurial start-ups as well as expertise in discovery informatics, computational science, and molecular design. H
Slide 65: Informatics enables rational design of better drugs
~1980 2D structure representations Early days of cheminformatics ~1985 – Today 3D structure from crystallography, computation Structure-based drug design Agenus – Future Direction 3D structure analysis of mAb/target complex Structure-based mAb optimization mAb (CDRs) Ag Informatics enables rational
Slide 66: 3D structure is key to understanding function
Topology is not a clear indicator of function – the protein fold assembles the biologically active elements. 3D structure is key to understanding function Agenus R&D Day | Nov 19, 2015
Slide 67: Enormous natural antibody diversity protects against myriad antigens
Enormous natural antibody diversity protects against myriad antigens Agenus R&D Day | Nov 19, 2015 Vary 6 residues at tip of each CDR loop (6x6 = 36 residues) Diversity space: 2036 = ~1047 possibilities → Too large to fully explore
Slide 68: Large, diverse libraries yield insights into structure and function
Large, diverse libraries yield insights into structure and function Next Generation Sequencing Genomics and bioinfomatics workflow Millions of Ab sequences Sample Raw NGS data NGS data process- ing Processed data Data Interpre-tation Interpreted data File size Can be TB size. Tab delimited text Docu
Slide 69: Structure guided libraries: unique competitive advantage
Rxx--loop--xDYW Cxx-loop-W YYCARxx-loop-xDYWGxG Rxx--loop loop--xDYW structural structural + structural = …YICGVGxTIxxQxVYVWGGG… KHYWQN… YFWLIA… EDQN… Rxx--loop--xDYW YYCAR YWGxG Cxx-loop-W xxCAR WVRQ LSCAA-loop-WVRQ xxYY GxGxx loop--xDYWGxGxx xxYYRxx--loop + Structural + Functional Motifs Unique co
Slide 70: Organizational complexity reflects biological function
2HEY OX40L-OX40 CRD1 CRD2 CRD3 CRD4 Organizational complexity reflects biological function Agenus R&D Day | Nov 19, 2015 Immune interactions
Slide 71: Receptor-ligand organization runs in families
Receptor-ligand organization runs in families – e.g., TNF-R family Agenus R&D Day | Nov 19, 2015 Representative class average 4-1BB / 4-1BBL complex TNF / TNFR complex OX40 / OX40L complex Won & Cho et al. 2010 J. Biol. Chem. Structure of the trimer of hu4-1BB Ligand …
Slide 72: Signaling requires micro-clusters at immune synapses
TM TM B7-1 CTLA4 N N 3osk Xray - huCTLA4 (ECD dimer) 1i8l Xray - huCTLA4 (ECD monomer) huB7-1 Signaling requires micro-clusters at immune synapses – CTLA4 “daisy chaining” Agenus R&D Day | Nov 19, 2015 huB7-1 (dimer) huCTLA4 (dimer) Omar S. Qureshi et al. 2011 Science …cell-extrinsic function of CTL
Slide 73: Antibody epitope corresponds to predictions
Antibody epitope corresponds to predictions CTLA4:B7-1 interface – Predicted epitope is unique to CTLA4 Confirmed by HDx experiments Different from the CD28 epitope Agenus R&D Day | Nov 19, 2015 Fab CDRs Epitope Surface CTLA4 huB7-1 (dimer) CTLA4
Slide 74: Structural and computational tools are helping us build better mAbs
Agenus R&D Day | Nov 19, 2015 Structural and computational tools are helping us build better mAbs Molecular understanding of antibody-antigen interactions enable us to selectively design and build differentiated antibodies with best-in-class potential.
Slide 75: Alex Duncan, PhD
Alex Duncan, PhD Alex Duncan is Vice President, Preclinical Development at Agenus Inc. He previously worked at Actigen where he was Managing Director and was responsible for several development project teams for immunomodulatory antibody compounds. Alex is a seasoned antibody research scientist and
Slide 76: Developing immuno-modulating oncology drugs is different
Developing immuno-modulating oncology drugs is ‘different’ Driven by Efficacy Development is faster Dosing lower Regimens shorter Combination studies earlier Faster development accelerates need for drug supply Agenus R&D Day | Nov 19, 2015
Slide 77: Changes in mAb discovery and development
Lead Generation Lead Optimization Drug Profiling IND Enabling Early Development Registrational Development Pilot Scale Process Commercial Scale Process (~ 3 years) ~7 years Changes in mAb discovery and development Agenus R&D Day | Nov 19, 2015 MANY CLONES ONE CANDIDATE Early Dev Reg Dev ~3 years The
Slide 78: What do we need to do to keep pace with clinical development?
What do we need to do to keep pace with clinical development? Agenus R&D Day | Nov 19, 2015 Commercial cell line/process at start of Phase III Qualification Runs Pilot scale with sub-optimal Process MANY CLONES ONE CANDIDATE “Best process for a given cell line” Manufacturability by antibody engineer
Slide 79: What are we doing to stay in front of the curve?
What are we doing to stay in front of the curve? Research Cell Bank Master Cell Bank Process Development Drug Substance “Fill-Finish” Drug Product Key Steps in GMP mAb Production Outsourced 7 weeks for clone generation 4 months to target cell line 24,000 sf Facility Disposable reactor technology ~2,
Slide 80: XOMA facility acquisition adds highly experienced team
XOMA facility acquisition* adds highly experienced team Establishment of product comparability (through different stages of production, transfer ) Working with / managing top tier CMOs CMC IND and BLA regulatory filings mAb Development, Characterization Experience GMP Manufacturing Experience (Phase
Slide 81: Impact of forward integration: flexibility, quality, control, savings
Flexibility: scheduling at facility fully under Agenus control Quality: full transparency, quality control; opportunity to innovate and optimize execution at facility Control: project re-prioritization at-will, no contractual delays at facility Speed: reduced time from development candidate to the c
Slide 82: Next Steps with Prophage in ndGBM
Next Steps with Prophage™ in ndGBM John M. Goldberg, MD Medical Director
Slide 83: John M. Goldberg, MD
John M. Goldberg, MD Dr. John Goldberg has served as Medical Director of Agenus Inc. since July 2015. Most recently, John came from the University of Miami Miller School of Medicine, where he was Associate Professor of Clinical Pediatrics, and Director of the Pediatric Oncology Early Phase Clinical
Slide 84: Topics in focus
Topics in focus Agenus R&D Day | Nov 19, 2015 Background on Prophage™ Effect of immunosuppression in ndGBM patients Development plans for Prophage
Slide 85: Immunity against cancer: the observations underpinning Agenus
Immunity against cancer: the observations underpinning Agenus Adapted from Srivastava 2002 Ann. Rev. Immunol. 20:395 Requires immune system Requires T Cells & NK Cells Agenus R&D Day | Nov 19, 2015 Tumor A mass is resected and Tumor B is administered
Slide 86: Heat-shock protein-neoepitope complexes confer immunity
Heat-shock Protein (HSP)-neoepitope complexes confer immunity hsp70 hsp90 hsp110 gp96 grp170 CRT HSP-containing fractions confer anti-cancer immunity Protein fractions from tumors Tumor Cells 7 14 0 Fractions tested in vivo in tumor rejection assays Mutated / Normal Cellular Peptides Chaperoning by
Slide 87: Prophage Phase 2 Trial in newly diagnosed Glioblastoma
ProphageTM Ph 2 Trial in newly diagnosed Glioblastoma (ndGBM) Investigators: Orin Bloch and Andy T. Parsa, UCSF Brain Tumor Research Center Agenus R&D Day | Nov 19, 2015
Slide 88: Prophage Phase 2 outcomes better than historic SOC
1 Stupp et al. 2005 2 Stupp et al. 2009 3 Single arm, open-label, study Comparison of Overall Survival (mOS) to Historical data * Phase 2 Cohort is a representative sample of resectable GBM patients Temozolimide (TMZ) ProphageTM – Phase 2 outcomes better than historic SOC Prophage + TMZ + Radiation
Slide 89: Local immunosuppression mediated by PD-L1 in glioma
Local immunosuppression mediated by PD-L1 in glioma (model) MACROPHAGE GLIOMA CELL CD8+ T-CELL Glioma cell releases cytokines, attracting macrophages Activated macrophages interact with CD8+ T-cells, including cell death via PD-L1/PD-1 interaction PD-L1 activated macrophages act as a defensive barri
Slide 90: Prolonged survival in less immuno-suppressed patients
Prolonged survival in less “immuno-suppressed” patients PD-L1more elevated : OS = 18 months PD-L1less elevated : OS = 45-47 months (follow-up continues) N=17 N=15 Overall Survival by Monocyte PD-L1 Expression Agenus R&D Day | Nov 19, 2015 Updated from Bloch et al. ASCO 2015
Slide 91: Prophage in ndGBM: results stratified by initial PD-L1 expression
Study PFS (months) mOS (months) Historical data* 5.0 – 9.0 14.6 – 18.8 Prophage in ndGBM Single arm, open label Ph 2 n=46 17.8 23.8 Prophage in ndGBM More Elevated PD-L1 on PBMs n=15 11.6 18.0 Prophage in ndGBM Less Elevated PD-L1 on PBMs n=17 27.0 44.7 ProphageTM in ndGBM: Results stratified by ini
Slide 92: Prophage: Potential rapid development path
Prophage™: Potential rapid development path* Patient entry Randomize Patient Enrollment Randomize Progression Physician Choice Survival FU Agenus R&D Day | Nov 19, 2015 PFS assessment 15-18 mos SOC + placebo SOC + vaccine vs. PD-1 vs. Endpoints: PFS, OS 120 patients *Proposed trial design pending re
Slide 93: Prophage + PD-1/PD-L1 blockade in ndGBM
Agenus R&D Day | Nov 19, 2015 Prophage™ + PD-1/PD-L1 blockade in ndGBM Combination studies between Prophage and PD-1 or PD-L1 blockers in patients with more elevated PD-L1 on PBMs: Increased immunosuppression mediated by glioma will be targeted specifically by inhibitors of the pathway Under active
Slide 94: Prophage in ndGBM: planned studies
Shows improved PFS, OS Less elevated PD-L1 patients likely to benefit most Targeted for study Spending boundary linked to futility analysis ~$10 million Immunosuppression in PD-L1 more elevated patients suggests role for combination immunotherapy Under active pursuit Agenus R&D Day | Nov 19, 2015 Pr
Slide 95: AutoSynVax: Next Generation Vaccines
AutoSynVax™: Next Generation Vaccines Leveraging NGS and informatics to produce a new class of autologous vaccines John Castle, PhD Senior Director, Bioinformatics & Genomics
Slide 96: John Castle, PhD
John Castle, PhD Agenus R&D Day | Nov 19, 2015 John Castle is the Senior Director of Bioinformatics of 4-Antibody, a subsidiary of Agenus Inc. After two years as a Research Scientist at MIT, he was appointed Associate Director at Rosetta Inpharmatics / Merck & Co. In 2009, he became Co-Director at t
Slide 97: Prophage and AutoSynVax
Prophage™ AutoSynVax™ Synthesize fully recombinant vaccines Prepare vaccine from patient tumor material Agenus R&D Day | Nov 19, 2015 AutoSynVax™ designed to extend what is achieved with Prophage™ Patient’s tumor Limited in quantity Unlimited quantities of vaccine
Slide 98: Agenus synthetic cancer vaccines to capture patient-specific mutations
Agenus synthetic cancer vaccines to capture patient-specific mutations Agenus R&D Day | Nov 19, 2015 AutoSynVax™ Concept Autologous cancer vaccine that recapitulates the benefits of ProphageTM when tumor material is insufficient for standard ProphageTM Exploits the Phase 2-validated HerpV rHSP70 pla
Slide 99: Agenus is uniquely positioned for synthetic cancer vaccines
Agenus is uniquely positioned for synthetic cancer vaccines Agenus R&D Day | Nov 19, 2015 Right targets Right format Right infrastructure AutoSynVax™ Concept Autologous cancer vaccine that recapitulates the benefits of ProphageTM when tumor material is insufficient for standard ProphageTM Exploits t
Slide 100: Prophage approach expanded to individualized cancer vaccines
Agenus R&D Day | Nov 19, 2015 The Prophage™ approach can be expanded to produce individualized cancer vaccines starting from INDIVIDUAL tumor genetic information Tumors harbor a unique set of genetic mutations, some of which can result in mutant proteins Tumor cells naturally degrade these mutant pr
Slide 101: The cost of genome sequencing continues to drop
Agenus R&D Day | Nov 19, 2015 The cost of genome sequencing continues to drop Forbes Magazine 2010 Unprecedented opportunity for personalized and individualized medicine 100,000.00 10,000.00 1,000.00 100.00 10.00 1.00 0.10 0.01 0.001 1990 2001 2007 2009 2012 13 years ~$3,000,000,000 <2 weeks ~$3,000
Slide 102: We can now determine the complete tumor mutation burden
Agenus R&D Day | Nov 19, 2015 PJ Stephens et al. Nature, (2012) Recurring tumor mutations Patient-unique tumor mutations Genes Occurrence of mutations across 100 individual breast cancer tumors Patient tumors We can now determine the complete tumor mutation burden Point mutations in red; copy number
Slide 103: Over 98% of mutations are unique to individual tumors
Mutated proteins Median per tumor Agenus, analysis of TCGA tumor profiles 10 500 Over 98% of mutations are unique to individual tumors Tumors typically contain 10-500 protein changing mutations Agenus R&D Day | Nov 19, 2015
Slide 104: A small fraction of mutations are immunologically significant
A small fraction of these mutations are immunologically significant Various carcinogens (sun, smoke, gamma rays, etc.) produce stochastic mutations (<0.03% of genome) A fraction of these produce potential T cell neo-epitopes – potential basis for immune rejection (1-20+) A handful hit growth-related
Slide 105: T cells destroy tumor cells displaying non-self neo-antigens
T cells destroy tumor cells displaying non-self neo-antigens Agenus R&D Day | Nov 19, 2015 Granules with perforins and granzymes Cell death by apoptosis
Slide 106: Connecting genetic mutations to recognized neo-epitopes is key
Connecting genetic mutations to recognized neo-epitopes is key Agenus R&D Day | Nov 19, 2015 Genetic mutations N ~1,000 Mutant peptide recognized by immune system N ~10 Peptide MHC Antigen prediction know-how & technology DNA
Slide 107: Leadership in the identification of immunogenic neo-epitopes
Leadership in the identification of immunogenic neo-epitopes Agenus R&D Day | Nov 19, 2015 MUT peptide binds stronger MUT and WT peptides bind equally WT peptide binds stronger True DNA mutation Not in subclonocal population Transcribed to RNA Translated to protein Processed by proteasomes Transport
Slide 108: Individualized cancer vaccine: preclinical proof of concept
Individualized cancer vaccine: preclinical proof of concept Sequence whole tumor genome B16 melanoma: 563 expressed missense mutations Predict and confirm peptide mutations 50 of 50 confirmed Immunize with mutant peptides Monitor response Confirm immune and clinical response ELISPOT Wild type & muta
Slide 109: AIM platform identifies neo-epitopes
A. Mutation identification C. Mutation immunological characterization B. Mutation functional characterization Patient-specific Candidates In silico neo-epitope annotator Ranked mutation-containing peptides Germline DNA Tumor DNA & RNA NGS data processing Expressed somatic mutations Molecular impact
Slide 110: Platform demonstrations with clinical samples
GBM PATIENT 123 GBM PATIENT 124 HLA types HLA-A*02:01 HLA-A*29:02 HLA-B*35:03 HLA-B*44:03 HLA-C*16:01 HLA types 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 (immunogenetic) Mutations 127 protein mutations 50 exp
Slide 111: AIM outputs a blueprint of neo-epitope peptides for GMP production
AIM outputs a blueprint of neo-epitope peptides for GMP production Agenus R&D Day | Nov 19, 2015 Patient 123 vaccine blueprint Sequences obscured for privacy Mutation & epitope 1ARNDCQEGHILKMFPSTWYVARNDCQEGHIL 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 …
Slide 112: AIM platform improvements and speed
Accuracy AIM v0.8 (Q1, 2015): platform as per Castle et al., 2012 AIM v0.9 (Q2, 2015): incorporation of class II binding AIM v1.0 (Q3, 2015): improved mutation prioritization AIM v1.1 (Q4, 2015): performance updates for IND In-house immunology & bioinformatics team for continual optimization Speed i
Slide 113: Putting AutoSynVax into patients
Putting AutoSynVax™ into patients Agenus R&D Day | Nov 19, 2015 We address the individuality Logistics NGS and high-performance computing infrastructure Rules for target identification Combine with QS21 and checkpoint antibodies
Slide 114: Wrap-up and Q&A
agenus viii. Wrap-up ix. Q&A