Driving the immune system to fight cancer and infectious disease. Jefferies 2015 Healthcare Conference

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1 a June Driving the immune system to fight cancer and infectious disease Jefferies 2015 Healthcare Conference 2015

2 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 Exchange Commission on March 31, 2015 and made available on our website at When evaluating Agenus business and prospects, careful consideration should be given to these risks and uncertainties. These statements speak only as of the date of this presentation, and Agenus undertakes no obligation to update or revise these statements. This presentation and the information contained herein do not constitute an offer or solicitation of an offer for sale of any securities. 2

3 Three Synergistic Immune-Modulating Platforms Goal: To Create Best-in-Class Immunotherapies + Ph 2 w Prophage in ndgbm + Ph 2 w HerpV Heat Shock Protein-Based Vaccines + Ph 3 Malaria + Ph 3 Shingles QS-21 Stimulon Adjuvant Checkpoint Modulators (CPMs) 3

4 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 4

5 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-3): 6%-12% royalty rate 50:50 cost and profit share programs (GITR, OX40) 5

6 Agenus Immuno-Therapeutics Overview

7 Agenus Pipeline *** *** *** *** ^ *** Partnered with INCY: GITR, OX40 agonist antibodies and TIM3, LAG3 antagonist antibodies ^ Partnered with Merck Partnered Not Partnered 7

8 Agenus Saponin Adjuvant Platform

9 QS-21 Stimulon Saponin Adjuvant Generates both antibody and cell-mediated immune responses Evaluated in clinical trials involving >30,000 patients Several product candidates under development at GSK Positive Phase 3 in Malaria 2014, at EMA Positive Phase 3 in Shingles December 2014 Agenus generally eligible to receive ~2% royalties on potential commercial sales 9

10 GSK Agenus Vaccine Collaboration: Focus on Shingles GSK Shingles Vaccine ZostaVax (Merck) Nature of vaccine Recombinant VZV glycoprotein E + QS-21 Live Attenuated Virus Efficacy at years in 50+ year olds 97.2% (n 16,700 1:1 placebo controlled) Efficacy at 1 year in year olds 70% Efficacy at 4 years in year olds 50% Efficacy at 1 year in 60+ year olds 50% Use in immuno-compromised Unlikely to be contra-indicated No Use in pregnancy Unlikely to be contra-indicated No Can Reactivate No Yes Approved by FDA for use in 50+ year olds TBD Yes Extensive experience with QS-21 adjuvant Positive Phase 3 in Malaria 2014, under review at EMA Positive Phase 3 in Shingles, reported December of 3 people will get shingles in their lifetime if reaching 80 years >1 of 5 people with shingles will develop Post-Herpetic Neuralgia Several additional clinical stage vaccine programs on-going 10

11 Heat-Shock-Protein (HSP)-based Vaccines A strategy for Tumor-Specific Immuno-education

12 The Immune System Can Defeat Cancer The Observations that led to Agenus TUMOR A CELLS INJECTED TUMOR A or B CELLS INJECTED Tumor mass is resected from mouse Mouse cured of tumor A immune to tumor A Naïve mouse Mouse forms tumor mass Mouse Cured Of Tumor A Requires immune system Requires T Cells & NK Cells Mouse cured of tumor A NOT immune to tumor B Mouse Cured Of Tumor A Adapted from Srivastava 2002 Ann Rev Immunol 20:395 12

13 Heat Shock Protein Fractions Elicit Immunity hsp70 hsp90 hsp110 gp96 grp170 CRT Tumor cell Proteins liberated from tumor cell Proteins tested in tumor rejection assays Heat Shock Proteins (HSP) elicit anti-cancer immunity DAY Rx 0 Rx Tumor Challenge 7 14 Tumor size MONITOR TUMOR GROWTH Days post tumor challenge 13

14 Heat Shock Proteins (HSPs) Quality Control for the Intracellular Proteome Cellular Peptides Mutated / Normal Chaperoning by HSPs Abundant class of intracellular proteins Constantly sample intracellular proteome Sense and manage misfolded proteins Natural role in immune recognition of damaged cells, nonself antigens 14

15 Prophage Mechanism of Action CD4+ T Cell CD8+ T Cell MCP-1 MIP-1 α RANTES NO IL-12 TNFα IL-1β GM-CSF NK Cell Modified from Srivastava Nature Reviews Immunology 2, (March 2002) 15

16 Prophage elicits tumor-specific immunity Tumor Heat Shock Protein bound tumor antigens APC Prophage Intradermal injection 16

17 HSP-based Vaccines Target Multiple Mutations And Function As Personalized, Patient-specific Immunotherapies Patient tumor Prophage individualized vaccine Purify heat-shock proteins (HSPs) complexed with muteins 17

18 Prophage in Newly Diagnosed Glioblastoma Multiforme

19 Glioblastoma Multiforme (GBM) GBM is the most lethal form of primary brain cancer ~27,000 annual new cases worldwide 1 Standard of care therapy is surgical resection followed by radiation & temozolomide Median overall survival on SOC ~ months 2,3 Two-year survival rate: 10-26%. Few patients survive beyond 5 years 1 1 CBTRUS 2012; 2 Stupp et al; N Engl J Med. 2005; 3 Stupp et al. Lancet Oncology,

20 GBM Mutational Burden Moderate, Variable Lawrence MS et al. Nature 2013; 499:

21 Prophage Production Under cgmp Resected tumor shipped frozen to Agenus Tumor homogenized & HSPs collected Approx. 1 dose of vaccine per gm of tumor Prophage Stable for 2 years at -80 C 21

22 Prophage in Newly Diagnosed GBM (ndgbm) Design: Phase 2, single arm, multicenter trial in surgically resectable, newly diagnosed GBM (N~50) Key Eligibility Criteria: 90% resection ; 6 vials of Prophage; KPS 70 Endpoints: Overall survival (OS), safety; progression free survival (PFS), immune response Concomitant RT + TMZ C o n f i r m Prophage Admin TMZ + Prophage Every 21 days through 24 Months or until vaccine depletion G B M 4 weekly admins WO 2-5 weeks 22

23 Prophage-Treated GBM Patients Show Longer mos Than SOC Probability of Overall Survival (%) Comparison of Overall Survival (mos) to Historical data Historical data Months Prophage + TMZ + Radiation 3 TMZ + Radiation (historical) 1,2 Radiation (historical) 1,2 mos=23.8 months (GTR) 3 mos=14.6 months 1 ; 18.8 (GTR) 2 mos=12.1 months 1 ; 14.2 (GTR) 2 1 Stupp et al Stupp et al Single arm, open-label, study *Phase 2 Cohort is a representative sample of resectable GBM patients 23

24 Proposed Immunosuppression by PD-L1 in Glioblastoma Multiforme 24

25 Prophage & CPMs in GBM: Potential Synergies Low baseline PD-L1 expression on PB monocytes and TIL macrophages correlates with prolonged PFS & mos after autologous HSP-based vaccination in ndgbm Prolonged PFS with Low PD-L1 monocyte expression PD-L1 low :Median PFS = 27.2 months Bloch O, Clinical Cancer Research 2013; AANS 2013 N=17 PD-L1 high : Median: PFS = 11.3 months N=15 Updated from Bloch et al. AANS

26 Prolonged Survival in Patients with Lower PD-L1 Monocyte Expression PD-L1 low : OS = months (follow-up continues) N=17 PD-L1 high : OS = 18 months N=15 Bloch et al, ASCO 2015 Prophage treated patients with low PD-L1 survive longer than historical comparators (15-19 mos) and best fit patients* (23-29mos) *Patients with MGMT methylation (Stupp et al., NEJM 2005 & LancetOnc 2009; Gilbert, NEJM 2013; Nabors et al, NeuroOnc 2015; Stupp et al, Lancet Onc 2014; Schuster et al., NeuroOnc 2015) 26

27 Prophage in Newly Diagnosed GBM Results Stratified by initial PD-L1 on PBMs Study PFS (months) mos (months) Historical data* Prophage in ndgbm Single arm, open label Ph 2 n=46 Prophage in ndgbm High PD-L1 on PBMs n=15 Prophage in ndgbm Low PD-L1 on PBMs n= *Stupp et al., NEJM 2005; AVAglio study, ASCO 2013; RTOG 0825, ASCO 2013; Westphal et al., Neuro-oncology; ICT-107 Phase 2, Wen et al., ASCO 2014 Bloch et al, ASCO

28 Prophage in ndgbm: Summary & Conclusions Significantly longer PFS & mos in Prophage+SOC patients with low initial PBM PD-L1 expression than in historical SOC trials High proportion have not progressed at ~4 years Is PD-L1 a predictor of response to Prophage? Is PD-L1 a predictor of better outcome independent of Prophage? Prophage effect observed regardless of MGMT status Benefit observed on top of MGMT methylation Patients do better than expected based on historical SOC responses Results warrant a Phase 3 controlled trial in ndgbm Results support exploration with PD-1 / PD-L1 blocking CPMs in those with high initial PD-L1 on PBMs 28

29 Prophage 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 29

30 Agenus Monoclonal Antibody Platform

31 Agenus Integrated Antibody Discovery Dedicated to Making Best in Class Antibody Drugs Target binding Retrocyte Display Fully human repertoire displayed on mouse pre-b cells 10 9 Antibody library Yeast Display (SECANT ) Display of full length IgG through biotin attachment 5x10 9 Antibody library Phage Display ScFv or Fab format Massive diversity >10 10 Differentiated screening options Effector Functions Fc-engineering Modulation of effector functions DuoBody bi-specific technology Computational Biology Bioinformatics Integrating structure and function data to understand MOA; Structureguided optimization; Epitope analysis MOA / Product Immuno-Biology Immunological assays can be leveraged across multiple TAs and used to determine appropriate isotype formats for product development Key components profiled Development Expertise Extensive internal development expertise Currently accessed through CRO 31

32 Key Components Retrocyte Display Retroviral transduction of human heavy and light chain antibody genes huigg V H Mouse pre-b cells huigg V L Ig-β Ig-α Ig-α Ig-β Natural folding, pairing, and anchoring Fully human high diversity stable antibody libraries Multiparameter screening methods Top Leads Iterations to identify high quality lead 32

33 Agenus Checkpoint Modulator Programs

34 Agenus Disclosed Checkpoint Modulator Programs Activating Receptors Inhibitory Receptors T Cells and other Immune cells Agonist Antibodies Agonist antibodies Antagonist Antibodies Antagonist antibodies Partnered with INCY: GITR, OX40 agonist antibodies and TIM3, LAG3 antagonist antibodies 34

35 Canonical View of GITR Forward Signaling in T Cells Initial priming Naïve T cell hrs GITR -L GITR expression upregulated Activated mature DC Secondary expansion No GITR stimulus GITR engagement Effector phase Reduced T cell expansion/survival Decreased cytokine production Enhanced effector T cell expansion/survival Increased proinflammatory cytokine production Adapted from: Current Opinion in Immunology

36 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:

37 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 Anti-GITR Isotype control CD4+ T cells 3% 3% 0% 1% 12% 2% CD8+ T cells 10% 11% 3% 3% IFN γ 12% 5% TNFα Reference: Agenus unpublished data Partnered with INCY: GITR, OX40 agonist antibodies and TIM3, LAG3 antagonist antibodies 37

38 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 Fold Cytokine Induction No antibody Isotype Ref Ab 1 Ref Ab 2 Agenus Agenus unpublished data Partnered with INCY: GITR, OX40 agonist antibodies and TIM3, LAG3 antagonist antibodies 38

39 Antibody Co-Engagement of FcγRs 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 GITR & OX40 agonist antibodies promote Teff resistance to Treg suppression GITR & OX40 agonist antibodies drive Teff activation/expansion 39

40 Checkpoint Modulators Combinations Will Be Critical CTLA-4 PD-1 LAG-3 OX-40 GITR TIM-3 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/Thy1 CD84/SLAMF5 CD28 CD40 Ligand CD96 CD229/SLAMF3 ICOS HVEM CD160 CRACC/SLAMF7 PD-L2/B7-DC LIGHT CD200 NTB-A/SLAMF6 PDCD6 DR3 OX-2R (CD200R) SLAM/CD150 B7-H6 TNF-alpha CD300a/LMIR1 Integrin alpha 4 beta 1 B7-H7 TNF-beta CRTAM Integrin alpha 4 beta 7/LPAM-1 BTLA (CD272) TNF RII DAP12 TCL1A KIRs BAFF/BLyS Dectin-1/CLEC7A TCL1B DNAM-1 (CD226) BAFF R DPPIV/CD26 TIM-1/KIM-1/HAVCR VSIG4 RELT EphB6 TIM-4 CD31 (PECAM-1) TACI HLA-DR TSLP PILR-α (FDF03) TL1A Ikaros TSLP R PILR-β TNRFSF25 Integrin alpha 4/CD49d A2AR SIRPα TIGIT ( WUCAM, Vstm3) Siglec-5 (CD170) RNF125/TRAC-1 CD47 CD155 Siglec-7 (CD328) CD5 LAIR-1 (CD305) CEACAM1 (CD66a) ILT2 MAFA BT3.1 CD33 ILT4 NKG2A BT3.2 EP4 (PGE2 receptor) EP2 (PGE2 receptor) NKG2B BT3.3 NKG2D Over 100 potential checkpoint proteins AGENUS HAS ADDITIONAL UNDISCLOSED CPM PROGRAMS 40

41 Agenus Immuno-Therapeutics Overview

42 Cancer- In Limbo between Self & Non-Self Mutational Heterogeneity in Cancer Taking off brakes may be enough Unclear how widely Immuno-Rx will work May need agonists, vaccines, adjuvants, etc. Lawrence MS et al. Nature 2013; 499: mutations per Mbase = 0.01% of genome 42

43 Checkpoints and Vaccines Synergize OX40 agonist and vaccine in mice Vaccine + CTLA-4 inhibitor (ipilimumab) give longer mos than either alone in prostate cancer mos Jensen et al., 2010 Semin Oncol. 37(5): Ipi monotherapy failed in Ph 3 (no stat. sign. vs. placebo) Importantly: 20% of patients alive at 80 months on PROSTVAC+ipi 10mg/Kg Source: 2015 Genitourinary Cancers Symposium, abstract no. 172; Bavarian Nordic press release 43

44 Realizing New Optimized Combination Strategies 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 Prophage SMIs 44

45 Balance Sheet (as of 3/31/2015) Unaudited Cash and short-term investments* $79.3 Other current assets 5.9 Net plant and equipment 5.8 Goodwill and acquired intangible assets 25.1 Other long-term assets 1.2 Total assets $117.3 Current liabilities $ 21.0 Long-term liabilities 31.2 Contingent obligations 18.8 Stockholders equity 46.3 Total liabilities and stockholders equity $117.3 * In May 2015, Agenus sold 12,650,00 shares of common stock in a public underwritten offering. Net proceeds were approximately $74.6 million. ($ millions) 45

46 Three Synergistic Immune-Modulating Platforms Goal: To Create Best-in-Class Immunotherapies + Ph 2 w Prophage in ndgbm + Ph 2 w HerpV Heat Shock Protein-Based Vaccines + Ph 3 Malaria + Ph 3 Shingles QS-21 Stimulon Adjuvant Checkpoint Modulators (CPMs) 46

47 Completed and Anticipated Milestones Milestones Anticipated Date CPM Partnership (Merck) 1H2014 Newly Diagnosed GBM Phase 2 Data 2H2014 Malaria BLA Filed in EU 2H2014 Shingles Phase 3 Data 2H2014 CPM Partnership (Incyte) Jan 2015 Phase 3 shingles data publication 2015 Submission of full Phase 2 ndgbm data for publication 2015 Initiate Prophage ndgbm Phase Potential EMA decision on malaria vaccine 2015 QS-21: GSK melanoma Phase 3 2 nd co-primary endpoint mid-2015 IND filings for GITR, OX40, CTLA4, PD-1, TIM-3, LAG /16 Initiate combination trials with vaccine and CPMs 2015/16 Leverage capabilities through further corporate partnerships Ongoing Initiate Phase 1 trials for first CPM product candidates

48 a June Driving the immune system to fight cancer and infectious disease Jefferies 2015 Healthcare Conference 2015